Lipoic acid (thioctic acid) has been reported to have utility for a wide range of therapeutic applications, including liver disease and poisoning (see DE-A-4338508), hypertension (see DE-A-4343647), pain and infection, especially retroviral infection such as HIV (see EP-A-0427247). It has been reported that (R)-lipoic acid is preferred for conditions associated with diabetes such as polyneuropathy and nephropathy (see DE-A-4343593), and for treating chronic degenerative diseases of the central nervous system (CNS) (see DE-A-4343592). Whereas in EP-A-0572922, it has been reported that a combination of the unnatural (S)-enantiomer and vitamin E provides effective analgesia. Thus, synthetic routes to single enantiomer lipoic acid have been sought.
There are already various synthetic approaches reported, such as in Y. S. Yadav et al, J. Sci. Ind. Rev., (1990) 49: 400-409; P. C. Bullman Page et al, J. Chem. Soc. Perkin Trans. 1, (1990), 1615-18; B. R. Menon et al, Tetrahedron Lett., (1987) 28: 2183-6; S. A. Gopalan and J. H. Jacobs, J. Chem. Soc. Perkin Trans. 1, (1990), 1897-1900; J. D. Elliot et al, Tetrahedron Lett., (1985) 26: 2535-8; M. H. Brookes et al, J. Chem. Soc. Chem. Commun., (1983), 1051-3; and L. G. Chebotareva, Zhim.-Farm. Zh.,(1980) 14: 92-9, including classical resolution; asymmetric epoxidation of an intermediate; enantiomeric control by a chiral auxiliary; or derivation from an available chirality pool material. The existing routes are generally not ideal as they involve many steps, use expensive reagents or starting materials, or result in loss of half the desired material following resolution of a racemate. As a result there is a continuing need for a more economical synthetic route.